Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a prevalent disease
that causes pelvic pain in men. While acute prostatitis is caused by bacterial
infection, the etiology of CPPS is unknown. However, Hou and colleagues have now
determined that an autoimmune response can cause prostatitis in mice (2031–2041).
Previous studies indicated that mice lacking autoimmune regulator (Aire), a
transcriptional regulator with a key role in establishing central tolerance, develop
prostatitis spontaneously. In this study, analysis of Aire-deficient mice revealed that
they mount a spontaneous T and B cell response to seminal vesicle secretory protein 2
(SVS2). The importance of the SVS2-specific immune response was highlighted by the
observation that wild-type mice immunized with SVS2 developed prostatitis. Of clinical
relevance, antibodies specific for the human SVS2-like seminal vesicle protein
semenogelin were detected in the serum of patients with CPPS. The authors therefore
suggest that CPPS is an autoimmune disease and that if this is confirmed, it will open
new avenues for diagnosing and treating CPPS, a condition for which there are currently
no specific treatments.

The appearance of binucleated tetraploid hepatocytes, as a result of a failure in
cytokinesis, is part of normal mammalian postnatal liver development. In this issue,
Celton-Morizur and colleagues have identified a cellular signaling pathway that leads to
cytokinesis failure and the formation of binucleated tetraploid hepatocytes in rodents
(1880–1887).
Initial analysis revealed that upon weaning, the proportion of dividing hepatocytes that
failed to complete cytokinesis increased substantially in rats. As rats with low levels
of circulating insulin and insulin-resistant mice both exhibited reduced formation of
binucleated tetraploid cells, while rats injected with insulin exhibited increased
formation of binucleated tetraploid cells, it seems likely that the aspect of the
suckling-to-weaning transition that controls the initiation of cytokinesis failure is
the increase in insulin levels that occurs upon weaning. Further in vitro analysis using
pharmacological inhibitors indicated that insulin controlled cytokinesis failure via the
PI3K/Akt signaling pathway. Future studies will investigate whether the deregulation of
the insulin signaling pathway observed in various metabolic diseases alters the liver
ploidy profile, and whether any modifications in this have a role in disease
pathophysiology.

Hemophilia A is an inherited bleeding disease caused by a lack of Factor VIII
(FVIII). It had been hoped that gene therapy would provide a treatment breakthrough, but
gene replacement strategies using viral vectors have been unsuccessful in clinical
hemophilia trials. However, Kren and colleagues have developed a nonviral, cell
type–specific gene-targeting system and used it to achieve long-term
expression of FVIII in hemophilia A mice, markedly reducing disease severity
(2086–2099).
Using a dispersion atomization method, the authors generated nanocapsules coated in
asialoorosomucoid (ASOR) or hyaluronan (HA) — ligands for cell-surface
receptors expressed uniquely by hepatocytes and liver sinusoidal endothelial cells,
respectively — and demonstrated their ability to target encapsulated
plasmids in a cell type–specific manner. Of therapeutic interest, when
hemophilia A mice were injected intravenously with HA-coated nanocapsules containing the
Sleeping Beauty (SB) transposon in
cis with the gene encoding B domain–deleted canine FVIII,
they exhibited plasma FVIII activity almost identical to that of wild-type mice through
50 weeks. As the hemophilia phenotype was markedly improved by treatment, the authors
hope this combination of technologies, the cell-specific nanocapsule delivery system and
the SB transposon, might constitute a viable gene therapy approach for
treating hemophilia A.

Studying individuals with paraneoplastic neurologic disorders (PNDs) such as Hu
syndrome, which can occur in individuals with small cell lung cancer (SCLC), provides
insight into human antitumor immunity. SCLC cells express the neuronal protein HuD, and
the presence of low-titer, HuD-specific antibodies correlates with improved prognosis
for individuals with SCLC. In a small number of patients, HuD-specific antitumor immune
responses also attack neurons, causing neurologic symptoms. As antigen-specific CTLs
have been detected in another PND, it has been proposed that HuD-specific
CD8+ T cells contribute to Hu syndrome pathogenesis, but such cells have
never been detected. However, Roberts and colleagues have identified, in Hu patients,
HuD-specific CD8+ T cells (2042–2051). Surprisingly, not all patients had the
same type of HuD-specific CD8+ T cells; some harbored classical
IFN-γ–producing CTLs, whereas others had atypical type 2
cytokine–producing, noncytotoxic CD8+ T cells, a finding that
provides a potential explanation for why these cells have been difficult to detect.
Further analysis indicated that SCLC cells produced type 2 cytokines and that these
cytokines promoted naive CD8+ T cell differentiation toward the atypical
phenotype, leading the authors to suggest this might be a mechanism by which SCLC evades
tumor immune surveillance.